DESCRIPTION (Verbatim from applicant's abstract): The title of the application is "Clinical and molecular analysis of Oregon Eye Disease." A more current title would be "Dystrophin and the retina." During the initial application period, it was shown that dystrophin, the product of the Duchenne muscular dystrophy (DMD) gene, is involved in retinal electrophysiology. Three lines of evidence support this. The position of a mutation in the DMD gene predicts the ERG phenotype, and abnormal ERGs were correlated in large part with mutations of a specific isoform of dystrophin, Dp260, which was identified and cloned from retina. New data suggests that other muscular dystrophies are associated with defects in retinal electrophysiology. Specifically, mouse models with defects in laminin-2 have abnormal ERGs. Dystrophin is part of a cellular continuum from the actin cytoskeleton to laminin and the extracellular matrix via a transmembrane group of proteins known as dystrophin-associated glycoproteins (DGC). It is hypothesized that defects in the interaction between retina-specific isoforms of dystrophin and the DGC result in altered retinal electrophysiology and an abnormal ERG. It is proposed that the retinal isoform Dp260 plays an important role in retinal electrophysiology by interfacing with the DGC at the photoreceptor to bipolar synapse. It is further proposed that dystrophin isoforms with non-overlapping cellular distributions have distinct roles in retinal function. Three specific aims will be performed to test these hypotheses, involving: (1) defining genotype-phenotype correlations for the DGC performing ERGs on both mutant mice and patients with defects in these proteins; (2) defining the specific cell synapse responsible for the ERG abnormalities demonstrated in the mdxCV3 mouse by in vitro cell-specific electrophysiology; and (3) delineating the diversity of dystrophin isoform expression in retina and to determining unique aspects of isoform structure and expression that may contribute to retinal electrophysiology. The long-term goals are to delineate the pathway by which dystrophin contributes to the normal ERG. By so doing, proteins will be identified, which when mutated, will be candidate genes for inherited retinal disorders associated with abnormal electrophysiology. Dystrophin and other proteins including members of the DGC will be targets for future gene therapy approaches.